Cellular basis of action of GI peptides. V.A. Chronic desensitization and down-regulation of the GRP receptor (GRP-R) are mediated by a PKC- dependent mechanism. The GRP-R undergoes chronic homologous desensitization and down-regulation, however, the mechanisms are unclear. To gain insight we prepared 5 mutant receptors: a COOH truncated mutant, a COOH terminal Ser/Thr free mutant, a COOH terminal PKC-consensus sequence (PKC-CS) deleted mutant, and 2 mutants that bound ligand but did not activate PLC. Our results suggested that activation of the distal COOH PKC-CS is essential for chronic desensitization and down-regulation of the GRP-R and provide no evidence for involvement of 2nd messenger independent processes. In contrast, internalization is equally regulated by both 2nd messenger-dependent and independent processes. V.B. The GRP receptor is phosphorylated by a non-PKC kinase after agonist exposure., Many protein-coupled receptors are phosphorylated post agonist exposure which modulates receptor activity. We investigated agonist-induced phosphorylation of the GRP-R antibody. Agonist-induced phosphorylation was rapid and we provide evidence that it is not caused by PKC- activation. V.C. Peptide structured requirements for high affinity interaction with the two mammalian bombesin receptors. There is minimal information on the peptide structural features determining specificity for the GRP-R or NMB-R. In the present study we used transfected cells possessing either receptor and examined the ability of natural occurring Bn-like peptides, NMB and Bn COOH terminal fragments and NMB analogues made more GRP-like by single amino acid substitutions (positions 3,6,9) as well as various conformationally restricted analogues to interact with each receptor subtype. Our results suggest that the active conformation of NMB differs markedly from the folded-beta-sheet model proposed for GRP, the structure-function differ markedly for the 2 receptors and suggest the NH2 terminus of GRP and NMB is important for receptor selectivity.